Study Protocol on Antimicrobial Stewardship in a Tertiary Respiratory Referral Hospital.

Background
Antimicrobial stewardship program is a comprehensive, longitudinal program designed to improve and measure the appropriateness of antimicrobial use while increasing patients' safety, decreasing cost of patients' care, and combating emerging antimicrobial resistance. Antimicrobial resistance, specially emerging multidrug-resistance and extremely drug-resistance gram negative bacteria, is an important concern in the modern world. This is particularly problematic since antimicrobials in production pipelines are not meeting the demand for the emerging resistance micro-organisms; in another word "we are running out of options". Indiscriminate use of antimicrobial may increase the risk for resistance, and drug toxicity. The aim of this study is to implement an evidence-based antimicrobial stewardship program in a tertiary referral hospital. This study will assure consistency of the stewardship program and measure outcomes to further assess the effectiveness of this program.


Materials and Methods
After establishment of antimicrobial stewardship committee and endorsement of policies the program will be conducted in all hospital medical wards. In an observational study, all patients receiving antimicrobials included in the program will be closely monitored for primary and secondary outcomes. Hospital's antimicrobial resistance patterns are monitored periodically to assess improvement. The quality indicators will be assessed to ensure proper execution of the program over time.


Results
As a study protocol, there are no results available to be reported at this time.


Conclusion
We are expecting to observe significant reduction in cost of antibiotic use shortly after program execution. By more appropriate utilization of antibiotics patients' safety will be increased. Furthermore, we are expecting to detect improvement in antimicrobial resistance patterns.


INTRODUCTION
Since early 20 th century, discovery of antibiotics have changed the practice of medicine, in a sense that once lethal infections, are now readily treatable. On one hand increased risk of morbidity and mortality is associated with inadequate empiric therapy in critically ill patients and on the other hand indiscriminate use of antibiotics in these patients promotes generation of resistance that can affect the whole population (1). By some estimates, up to 50% of antimicrobial drugs are used unnecessarily or inappropriately (2). Emergence of resistance, toxicity, prolonged hospital length of stay, increased morbidity and Resistance to antimicrobials is a growing threat to public health because specific treatment options are limited for the emerging multidrug and extremely drug resistant species (4). Moreover, analysis of antibiotics development pipeline raises a serious concern on lack of new antibiotics of emerging resistant organisms (5  This ASP will be initiated in a respiratory tertiary referral hospital, aiming to optimize antimicrobial use, combat antimicrobial resistance, and increase quality of care while decreasing cost of care.

A) Antimicrobial Stewardship Policy:
Hospital shall develop its local policy. Antimicrobial Stewardship Committee (ASC) must be established and all stewardship policies must be endorsed by the committee.
Policies must then be publicized to the whole facility by hospital director. The policy shall include the following: 1. Ratification of a list of antimicrobial agents that must be included in the ASP. Primarily broad spectrum antibiotics will be included in the program, which

B) Core Strategies:
I) Antimicrobial Stewardship Team and Leadership: Core members of a multidisciplinary antimicrobial stewardship team will include an infectious disease physician and a clinical pharmacist with infectious disease training, and a clinical microbiologist. The ASP team will further include an information system specialist (14). The Overall trend of antimicrobial use must be monitored periodically since in this method antimicrobial utilization may shift to alternative agents (2).

Prospective audit with intervention and feedback
Prospective Audit and Feedback (PAF) with direct interaction of an infectious disease physician by medical consult and giving direct feedback to the prescriber will be used to increase compliance to local guidelines (17).

C) Supplemental Strategies:
I) Implementation of facility-specific clinical practice guideline: Facility-specific treatment recommendations will be developed and implemented based on national guidelines and local susceptibility for common infectious disease syndromes. Local antimicrobial susceptibility pattern will be considered when initiating empiric therapy for specific infections. Local guidelines will be endorsed by ASC and be announced by ASP leader to hospital clinicians (18).

II) Antimicrobial "Time out":
Implementation of antimicrobial "time out" or stop order will further oblige clinicians to revise antimicrobial agents after 72-hours of initiation. Computerized decision support at the time of prescribing will be incorporated as a part of ASP to facilitate time-sensitive stop order implementation (14).

III) Pharmacy-driven interventions:
Clinical pharmacist consult to perform dose adjustments for patients with organ dysfunction in order to optimize the dose and frequency of drug therapy will be performed (18).

IV) Educational interventions:
Educational interventions will be incorporated into ASP through passive activities like conference presentations for hospital personnel and clinicians (19).

D) Strategies for Optimization of ASP:
I) Pharmacist-driven pharmacokinetic drug monitoring and dose optimization will be implemented as a part of ASP program for aminoglycosides and vancomycin (18).

II) Guideline for appropriate initiation of oral antibiotics
and timely transition of patients from IV to oral antibiotics will be designed and implemented in hospital (20).

G) Process and Outcome Measures:
Excess days of therapy, duration of therapy, proportion of patients receiving therapy as per facility guideline or algorithm, will be assessed and ASP should be revised based on these data. Microbiology guideline, and proportion of patients converted to oral therapy can be used as measures to assess process of ASP.
Furthermore, hospital length of stay, 30-day mortality, unplanned hospital readmission within 30 days, proportions of patients with clinical failure (eg, need for broad spectrum antimicrobial, recurrence of infection), proportion of patients diagnosed with C. difficile or adverse events related to antibiotic treatment, and also the percent of antibiotic resistant healthcare-associated pathogens prevalence will be employed to measure ASP outcomes.

DISCUSSION
Our antimicrobial stewardship program will be implemented with the aim to improve hospital's quality of patient care; while combating the bacterial resistance which is a major concern in the healthcare system (8). ASPs are dedicated to improve antimicrobial use both through optimization of treatment and by reducing antimicrobial related adverse events (9). These programs can be utilized to further improve patient safety by reducing treatment failure, increasing rationalized use of antibiotics and cure rates (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).
Longitudinal study of ASP outcome measures and quality indicators will guarantee sustainability and effectiveness of the program.